Institute of Applied Physiology, University of Ulm, Germany

bCentre for Integrative Physiology, University of Edinburgh,Edinburgh, UK

AbstractDopamine (DA) releasing midbrain neurons are

essential for multiple brain functions, such as voluntarymovement, working memory, emotion and cognition. DAmidbrain neurons within the substantia nigra (SN) and theventral tegmental area (VTA) exhibit a variety of distinct axonal projections and cellular properties, and are dierentiallyaected in diseases like schizophrenia, attention decithyperactivity disorder, and Parkinsons disease (PD). Apartfrom having diverse functions in health and disease states,DA midbrain neurons display distinct electrical activitypatterns, crucial for DA release. These activity patterns aregenerated and modulated by specic sets of ion channels.Recently, two ion channels have been identied, not onlycontributing to these activity patterns and to functionalproperties of DA midbrain neurons, but also seem to renderSN DA neurons particularly vulnerable to degeneration inPD and its animal models: L-type calcium channels (LTCCs)and ATP-sensitive potassium channels (K-ATPs). In thisreview, we focus on the emerging physiological andpathophysiological roles of these two ion channels (and theircomplex interplay with other ion channels), particularly inhighly vulnerable SN DA neurons, as selective degenerationof these neurons causes the major motor symptoms of PD. 2014 The Authors. Published by Elsevier Ltd. on behalf ofIBRO. This is an open access article under the CC BY-NC-NDlicense (http://creativecommons.org/licenses/by-nc-nd/3.0/).

http://dx.doi.org/10.1016/j.neuroscience.2014.10.0370306-4522/ 2014 The Authors. Published by Elsevier Ltd. on behalf of IBRO.This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).798

DISTINCT ACTIVITY PATTERNS OF SN DA

NEURONS ROLE OF ION CHANNELSIn order to fully comprehend the crucial roles of ionchannels for SN DA function in health and disease, oneneeds to understand their fundamental role for thegeneration of neuronal electrical activity patterns. SNDA neurons are spontaneously active (Grace andBunney, 1984a,b), and their tonic action potential ringis crucial for DA release from striatal axon terminals aswell as from soma and dendrites of SN DA neurons(Rice et al., 2011). In vivo, within the intact basal ganglia

Simon et al., 2010). It is noteworthy, that in all of these

three studies, no stratication for exclusive DHPtreatment was made, but data were pooled for bothDHP and non-DHP calcium channel blockers.In neurotoxic animal models of PD (MPTP, 6-OHDA),DHP LTCC blockers indeed seem to protect SN DAneurons from degeneration in mice (Kupsch et al., 1995;Chan et al., 2007) and non-human primates (Kupschet al., 1996) in a dose-dependent manner (Ilijic et al.,2011), but these ndings need to be conrmed in furtherstudies. The systemic DHP-plasma levels reached inmice for SN DA protection seem to be similar to thosedescribed in humans when treated for high blood pressure (24 ng/ml in mice and 12 ng/ml in humans at10 mg/day (Surmeier et al., 2011; Surmeier andSchumacker, 2013)). It is noteworthy that the humanepidemiologic or mouse in vivo studies show a SN DAprotective eect of systemic LTCC-blockers, but they donot demonstrate that this protective eect is a directconsequence of inhibiting SN DA LTCCs and relatedcalcium signaling at these therapeutic plasma levels.However, work from Surmeier and colleagues provides

that T2D and PD might share similar disease pathways

(Santiago and Potashkin, 2013). To our knowledge,K-ATP channel blockers are currently not systematicallytested as a novel neuroprotective strategy in PD. Andsimilarly as for LTCCs blockers, given the widespreadfunctional expression of K-ATP channels, SN DA andK-ATP subtype-specic drugs would be desired.However, the NMDA-R antagonist memantine is in trialfor PD therapy and seems to be benecial (Emre et al.,2010). Interestingly, memantine also acts as a K-ATPchannel blocker, and aect SN DA burst ring, independently of NMDA-R function (Giustizieri et al., 2007).

function, but they generate an activity-related metabolic

burden for those neurons (Ca2+, ROS and NO levels)that renders them particularly vulnerable to PD-triggersand degeneration. Consequently, as summarized inFig. 2A, a variety of backup mechanisms are present inSN DA neurons to control and counteract LTCC andK-ATP channel-triggered overexcitability and excitotoxicity(D2-AR/GIRK2, SK3, A-type K+ channels, K-ATPchannels), or to counteract Ca2+, metabolic stress andROS (e.g. SOD, UCPs, DJ-1/PARK7, (Guzman et al.,2010; Surmeier et al., 2012)). Under physiologicalconditions, this complex network of activity-controlling ionchannels and metabolic protection pathways, in interplaywith ER and mitochondrial Ca2+ buering, allows LTCCand K-ATP channel function in SN DA neurons withouttriggering degenerative pathways (Fig. 2A).However, what happens if PD-triggers furthercontribute to this intrinsic metabolic stress of SN DAneurons? These triggers could be intrinsic PARK-genemutations (such as DJ-1), or increased age and agerelated mitochondrial dysfunction, or extrinsic factors,such as environmental toxins (e.g. rotenone MPTP), orPD-related alterations in glutamatergic synaptic input(Rodriguez et al., 1998; Hardy, 2010; Meredith andRademacher, 2011).As illustrated in Fig. 2B, all these PD-triggers cansynergistically increase mitochondrial dysfunction, generalmetabolic stress and intracellular free calcium load,ROS and NO levels. At this point, a vicious circle couldtake its course, by further stimulating mNOS/NO-levels,and thus not only possibly reduce ETC activity(Sanchez-Padilla et al., 2014), but also elevate superoxide levels, further increasing mitochondrial stress, asdescribed above (Surmeier et al., 2010; Sanchez-Padillaet al., 2014). NO itself as well as ROS / mitochondrialdysfunction will further increase the open probability ofK-ATP channels (Zhang et al., 2001; Lin et al., 2004),which until a certain point will stimulate stressful bursting of SN DA neurons, and thus further drive the viciouscycle of Ca2+ load, metabolic stress and excitotoxicitythat can no longer be properly controlled by the describedinhibitory feedback mechanisms. On the other hand,in a chronic interplay of increased Ca2+-dependentD2/GIRK2 and A-type K+ channel activity, furtherK-ATP channel activation would rather lead to a chronicreduction of SN DA activity, as described above, and thuslikely lead to a reduction of activity-dependent vitalfactors, like brain-derived neurotrophic factor (BDNF)(Hyman et al., 1991; Kurauchi et al., 2011; Peng et al.,2011). In either scenario, the inhibitory feedback systemsin SN DA neurons, likely serving to protect from metabolically precarious physiological LTCC and K-ATP activityand related pathophysiological overexcitability, wouldeventually fail in the chronic presence of too high levelsof metabolic stressors in PD, ultimately leading to theselective death of SN DA neurons.

CONCLUSIONSThe pathological hallmark of PD, which causes the majormotor-related symptoms of the disease, is the selective

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loss of mesostriatal SN DA neurons. There is clear

evidence that physiological LTCC (in particular of theCav1.3 type) as well as K-ATP channel (made up byKir6.2/SUR1 subunits) function contribute to metabolicstress and the selective high vulnerability of SN DAneurons to degeneration in PD and its animal models.Nevertheless, these channels in SN DA (but not in VTADA) neurons seem to be crucial for their distinctelectrical activity patterns, their physiological signaling(e.g. calcium-dependent enzyme activation andregulation of gene expression), and their relatedcomplex functions within the basal ganglia network (e.g.novelty-related behavior). However, physiological K-ATPand LTCC activity generates an intrinsic high metabolicburden for SN DA neurons, due to associated burstactivity and activity-dependent elevated intracellularCa2+ levels. We hypothesize that consequently, acomplex network of inhibitory feedback mechanisms ispresent in SN DA neurons to control physiologicalLTCC and K-ATP channel function and tohomeostatically tune SN DA activity pattern to themetabolic states of these neurons, to thus circumventoverexcitability and excitotoxicity. Ca2+-dependentsensitization of inhibitory D2-AR/GIRK2 signaling as wellas Ca2+-dependent A-type K+ channel signaling in SNDA neurons provide just two distinct potential feedbackmechanisms.However, activity patterns of SN DA neurons arecontrolled by a variety of additional ion channels andreceptors (compare Fig. 1), and thus this network iseven more complex than described here. To furtherillustrate the complexity, recent evidence showsfunctional coupling of voltage-gated T-type Ca2+channels with A-type K+ channels (Kv4.3) via Ca2+levels and KChip3 (Anderson et al., 2010; Turner andZamponi, 2014), and we gained evidence for an interplayof TTCCs with LTCCs and K-ATPs. Not only in this context, it is very important to systematically study the cellspecic contributions of other voltage-gated calciumchannels (like P-, N-, Q-, R-, and T-type channels(Catterall et al., 2005)) to SN DA function in health andPD. In view of desired novel neuroprotective PD-therapies, these ion channels provide promising potential targets, in addition to LTCC-blockers, which are already inclinical trials (Parkinson Study, 2013). However, as allthese channels are not only expressed in SN DA neurons,but in a variety of other neuronal and non-neuronal cells,the development of channel subtype-specic blockersthat ideally selectively target SN DA neurons, is desired.Future research is needed to develop those blockers,and to address acute and chronic pathophysiological consequences, as well as side eects of pharmacologicalmodulation of the emerging complex network of ionchannel functions in SN DA neurons, as potential noveltherapeutic strategies in PD.

FUNDINGThis work was supported by the DFG (SFB497, LI-1745and CEMMA), the Austrian Science Fund (FWF SFBF4412), the BMBF (NGFN, 01GS08134), the Alfried

Krupp prize (all to BL), and the Leopoldina fellowship

program (LPDS 2012-11 to J.S.).AcknowledgementsWe are particularly grateful to the braindonors and the support by the German BrainNet (GA28). Wethank Joerg Striessnig and James D. Surmeier for critical readingof the manuscript.